Orodispersible pharmaceutical composition of an antithrombotic compound

ABSTRACT

The invention relates to a solid orodispersible pharmaceutical composition of an antithrombotic compound (compound A), characterised in that it comprises compound A or a pharmaceutically acceptable salt thereof and granules consisting of co-dried lactose and starch.

The present invention relates to a solid orodispersible pharmaceuticalform for the administration of an antithrombotic compound or apharmaceutically acceptable salt thereof by the oral or buccal route.

The antithrombotic compound, hereinafter referred to as compound A,which is described in patent specification EP 648 741, is the compoundof formula (I):

Compound A can be administered by the oral route in the form of tabletsto be swallowed with half a glass of water.

The doses of compound A used by the oral or parenteral route to obtainthe therapeutic effect generally range from 10 mg to 30 mg peradministration, one or more times per day, in the form of animmediate-release tablet.

Many people have difficulty in swallowing conventional tablets, the sizeof which is often not negligible. The problems associated with theingestion of medicines (choking; suffocation as a result of obstructionof the throat) are often the cause of poor compliance with dosageregimens or, indeed, of discontinuation of treatment.

The pharmaceutical compositions of the present invention make itpossible not only to solve the known problems of a tablet form that hasto be swallowed but also to offer a superior medical service whichespecially allows the quality of life of patients to be improved.

The orodispersible pharmaceutical composition of compound A has theadvantage that elevated plasma levels of active ingredient are obtainedrapidly and, moreover, by virtue of its rapid disintegration, makes itpossible to limit the variations in absorption, which may be caused byvarious factors.

The orodispersible pharmaceutical composition according to the inventionhas the particular characteristic of requiring neither water nor chewingin the course of its administration. It disintegrates very rapidly inthe mouth, preferably in less than three minutes and even morepreferably in less than one minute.

Many rapid-dissolution forms are described in the prior art. In general,it is common to the previously described technologies that they use adisintegrating agent such as Kollidon® CL (crosslinkedpolyvinylpyrrolidone), EXPLOTAB® (carboxymethyl starch) and AC DISOL®(crosslinked sodium carboxymethylcellulose).

That disintegrating agent is indispensable to the formulation of theorodispersible tablets and has to be used in conjunction with adirect-compression excipient. The difficulties encountered in themanufacture of such tablets reside in the fact that it is very difficultto obtain tablets having physical characteristics that are constant andreproducible and compatible with the customary handling requirements oftablets.

However, the customarily used mixtures result in tablets of veryconsiderable hardness which is completely unsuitable for rapiddisintegration in the oral cavity.

Other orodispersible forms can be produced by using lyophilisation,resulting in very porous solid forms called “oral lyophilisates”. Thoseforms require the use of a highly specific and complicated industrialprocess which is lengthy to carry out, yielding a medicament form whichhas a high cost price.

The present invention enables those problems to be solved. It relates toa solid orodispersible form of compound A, optionally in the form of anoptical isomer, or a pharmaceutically acceptable salt thereof,comprising a single excipient of natural origin which allows rapiddisintegration and which has a neutral flavour and agreeable texture.The said excipient acts both as binder and as disintegrant. It allows asimple formulation of compound A to be obtained, having excellentsuitability for direct compression, resulting in tablets of lowfriability and of a hardness that is compatible with customary handlingmethods.

More specifically, the invention relates to a solid orodispersiblepharmaceutical composition of compound A or a pharmaceuticallyacceptable salt thereof, characterised in that it comprises:

-   -   compound A or a pharmaceutically acceptable salt thereof,    -   and granules consisting of co-dried lactose and starch.

Compound A preferably has the absolute configuration (R).

Preference is given to compound A being in the form of a sodium salt.

The composition according to the invention may also comprise, forreasons of manufacture, one or more lubricants and a flow agent and, forreasons of masking taste or bitterness, flavourings and sweeteningagents as conventionally used.

In order to improve masking of the bitterness of compound A, the lattermay optionally be associated with excipients such as cyclodextrins orcoated with excipients using technologies known to the person skilled inthe art such as, for example, coating in a fluidised-air bed,atomisation, coacervation, prilling and spray-congealing.

The invention relates also to the use of granules consisting of co-driedlactose and starch in the manufacture of solid orodispersiblepharmaceutical compositions of compound A.

The term “orodispersible” is understood to refer to solid pharmaceuticalcompositions which disintegrate in the oral cavity in less than 3minutes, preferably less than one minute.

The said granules present in the solid pharmaceutical compositionsaccording to the invention correspond to the compositions described inPatent Application EP 00/402159.8. Those granules are characterised by aspherical structure and an advantageous compressibility and are marketedunder the name STARLAC®.

The disintegrating properties of the said granules are known for tabletsplaced in large volumes of stirred liquids. It is especially surprisingthat, when used in the manufacture of orodispersible forms, the saidgranules should give especially satisfactory results in terms ofdisintegration in the mouth, for two reasons.

The first reason is based on the finding that the least water-solubleexcipients are the most suitable for the formulation of orodispersibletablets (dissolution, in bringing about an increase in the viscosity ofwater, slows down its penetration into the tablets) and yet the saidgranules contain a large amount of highly water-soluble lactose.Moreover, the starch contained in the said granules is not a“super-disintegrant” agent as used and described in the orodispersibleforms of the prior art.

The second is based on the finding that the disintegrant properties ofan excipient (used in a tablet), when determined in water usingconventional methods, cannot be extrapolated to the behaviour of thesame tablet in vivo, in saliva. Disintegration rates in water aremeasured (in accordance with the European Pharmacopoeia) in an amount ofwater that is sufficiently large not to reach saturation level in termsof dissolution, whereas in vivo, by virtue of the small volume ofsaliva, the excipients are at saturation level. Furthermore, thestirring to which the tablets are subjected in the customary test doesnot reflect disintegration in the mouth. The Applicant accordinglyfound, during comparative tests, that certain excipients which are knownas good disintegrants are not suitable for the preparation oforodispersible forms. Conversely, certain excipients that exhibitaverage disintegration in water may exhibit advantageous properties invivo.

The Applicant then found, surprisingly, that the said granules renderedthe tablets highly suitable for disintegration in the mouth, that beingthe case over a wide range of tablet hardness, whilst maintaining a lowlevel of friability, which is especially remarkable. Most orodispersibleforms of the prior art which disintegrate rapidly in the mouth arehighly friable, which is reflected in the need to use a specificpackaging and the risk of the tablet disintegrating as soon as it ishandled and taken out of its pack.

It is especially remarkable that the above-mentioned criteria oforodispersibility and low friability are maintained over a wide range oftablet hardness, that is to say for tablets having a hardness of from 15to 30 Newtons.

The pharmaceutical compositions according to the invention arepreferably characterised in that they comprise, in relation to the totalweight of the tablet:

-   -   from 2.5% to 20% by weight of compound A or a pharmaceutically        acceptable salt thereof, preferably from 5% to 10%,    -   from 75% to 95% by weight of STARLAC®.

They may optionally comprise from 0.1% to 3% by weight of lubricatingagents such as magnesium stearate, preferably from 0.5% to 1.5%, andfrom 0.1% to 3% by weight of a flow agent such as colloidal silica,preferably from 0.5% to 1.5%.

The following Examples illustrate the invention without limiting it inany way.

The orodispersible tablets were produced using the (R) isomer ofcompound A, in the form of a sodium salt.

EXAMPLE 1

Formulation: Finished Tablet of 100 mg Constituents Amount (mg) CompoundA, sodium salt 10*   Starlac ® 88.25  Magnesium stearate 1   Anhydrouscolloidal silica 0.25 Aspartame 0.25 Acesulfame K 0.25*expressed as compound A in the form of the base

EXAMPLE 2

Formulation: Finished Tablet of 300 mg Constituents Amount (mg) CompoundA, sodium salt 30*   Starlac ® 264.75  Magnesium stearate 3   Anhydrouscolloidal silica 0.75 Aspartame 0.75 Acesulfame K 0.75*expressed as compound A in the form of the base

The tablets are prepared by mixing the constituents, followed by directcompression. The hardness of the tablets of Examples 1 and 2 is about 15Newtons and 30 Newtons, respectively.

In order to determine the disintegration time in the mouth, theorodispersible tablets of compound A described in Examples 1 and 2 wereplaced in the mouth. In these tests it was found that, for each of theformulations tested, the disintegration time in the mouth was less than1 minute.

1-12. (canceled) 13- A solid orodispersible pharmaceutical compositioncomprising compound A of formula (I), optionally in the form of anoptical isomer, or a pharmaceutically acceptable salt thereof:

and granules consisting of co-dried lactose and starch. 14- Thecomposition according to claim 13, wherein the composition disintegratesin the mouth in less than three minutes. 15- The composition accordingto claim 14, wherein the composition disintegrates in the mouth in lessthan one minute. 16- The composition according to claim 13, whereincompound A has the (R) configuration. 17- The composition according toclaim 13, comprising, in relation to the total weight of thecomposition: from 2.5% to 20% by weight of compound A or apharmaceutically acceptable salt thereof, and from 75% to 95% by weightof granules consisting of co-dried lactose and starch. 18- Thecomposition according to claim 17, comprising from 5% to 10% by weightof compound A or a pharmaceutically acceptable salt thereof. 19- Thecomposition according to claim 13, wherein compound A is in the form ofa sodium salt. 20- The composition according to claim 13, furthercomprising one or more flavourings and sweeteners. 21- The compositionaccording to claim 13, further comprising one or more lubricants and aflow agent. 22- The composition according to claim 13, wherein thecomposition is in the form of a tablet. 23- The tablet according toclaim 22, wherein the tablet is obtained by direct compression. 24- Thetablet according to claim 23, wherein the tablet has a hardness from 15to 30 Newtons. 25- A process for the manufacture of solid orodispersiblecompositions of compound A, or a pharmaceutically acceptable saltthereof, which disintegrate in the mouth in less than three minutes,wherein compound A, or a pharmaceutically acceptable salt thereof, ismixed with granules consisting of co-dried lactose and starch. 26- Aprocess for the manufacture of solid orodispersible compositions ofcompound A, or a pharmaceutically acceptable salt thereof, whichdisintegrate in the mouth in less than one minute, wherein compound A,or a pharmaceutically acceptable salt thereof, is mixed with granulesconsisting of co-dried lactose and starch. 27- A method for treating aliving animal body, including a human, afflicted with a conditiontreatable by an antithrombotic agent, comprising the step ofadministering to the living animal body, including a human, acomposition according to claim 13 which is effective for alleviation ofthe condition.